Phosphate is present in the plasma, intracellular fluid, cell membranes, collagen and bone tissue of mammals. It is a dynamic constituent of energy metabolism, an essential component of skeletal mineralization, a modulator of tissue concentrations of calcium, and plays a major role in renal excretion of H.sup.+.
Phosphate homeostasis in mammals is a balance between intake, intestinal absorption, bone deposition/resorption, and renal excretion and resorption. An excess of phosphate reduces the circulating Ca.sup.2+ levels, and a deficit results in decreases in erythrocyte ATP and 2,3-diphosphoglycerate and contributes to the pathology of osteomalacia, hypocalciuria, and rickets. Dietary phosphate is absorbed from the gastrointestinal tract in an active, energy-dependent process that is modified by hormones, vitamin D, Ca.sup.2+, and Al.sup.3+. Regulation of the serum concentration of phosphate is maintained through resorption by the sodium phosphate cotransport system, located in the proximal convoluted renal tubule. Local concentration of phosphate in specific tissue types, such as liver, bone, and brain, is modulated by sodium phosphate transport proteins located in these tissues. (Hartmann, C. et al. (1996) Proc. Natl. Acad. Sci. 93:7409-7414; Glinn, M. et al.(1995) J. Neurochem. 65:2358-2365).
Human NPT1, NPT2, NaP.sub.1 -3, and the X-linked hypophosphatemia (PEX) sodium phosphate transport proteins are found in the renal brush border membrane where they participate in renal tubular phosphate uptake. Although similar in function, these renal proteins differ in affinity, capacity, map to different chromosomal locations, and are differentially regulated by hormones and dietary phosphate (Tenenhouse, H. (1989) Biochem. Biophys. Acta 984: 207-213; Fulceri, R. (1993) Biochem. J. 289:299-306; Chong, S. et al. (1993) Genomics 18:355-359; Miyamoto, K. et al. (1995) Biochem. J. 305:81-85).
Sodium phosphate transport proteins in rat brain neurons regulate intracellular phosphate concentrations necessary for maintaining the phosphorylation potential of the cell. Physiological concentrations of phosphate enhance the ATP-dependent binding of Ca.sup.2+ to brain microsomes, resulting in a larger intracellular pool of Ca.sup.2+ released by inositol triphosphate. The expression of the brain specific sodium-dependent phosphate transporter, rBNPI, is developmentally regulated and is specific to neuron enriched regions of the adult rat brain. Avian osteoclasts express a sodium-dependent phosphate transporter regulated through integrin-mediated pathways in the presence of bone. This transporter is hypothesized to act in the transcellular movement of phosphate during active bone resorption (Ni, B. (1995) J. Neurosci. 15: 5789-5799; Gupta, A. (1996) Kidney Int. 46: 968-974).
By low stringency screening of a human kidney cortex cDNA library with a rabbit NaP1-1 cDNA, Chong et.al. (1993, supra) isolated a cDNA encoding a human sodium-dependent phosphate transport protein (NPT1). Localization of NPT1 to 6p23-p21.3 was found by Southern hybridization to HindIII-digested DNA from a human chromosome 6 somatic cell hybrid deletion panel. Fluorescence in situ hybridization maps NPT1 to 12p11 in the rabbit. This assignment agrees with the previously reported homology between rabbit chromosome 12 and human chromosome 6 (Kos, C. et al. (1994) Genomics 19: 176-177).
The discovery of proteins related to human renal sodium phosphate transport protein, and the polynucleotides encoding them, satisfies a need in the art by providing new compositions useful in diagnosis and treatment of diseases associated with increased or decreased phosphate levels.